Cardiovascular Hazards of Abacavir- Versus Tenofovir-Containing Antiretroviral Therapies: Insights From an Analysis of the REPRIEVE Trial Cohort

Background: Prior analyses suggest that the nucleoside reverse transcriptase inhibitor (NRTI) abacavir (ABC), but not tenofovir (TFV), is associated with a 2-fold increase in the hazard of myocardial infarction. the Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE) is ideally suited to evaluate the role of ABC and the TFV backbones, tenofovir alafenamide (TAF) and tenofovir disoproxil fumarate (TDF), in major adverse cardiovascular events (MACE). Methods: We compared hazard of first MACE among people living with human immunodeficiency virus (HIV) at low-to-moderate cardiovascular risk using ABC (n = 883), TAF (n = 957), and TDF (n = 4274) at entry. Overlap weights balanced biasing factors, including age, sex at birth, atherosclerotic cardiovascular disease risk, CD4 count, estimated glomerular filtration rate, and anchor antiretroviral therapy. Associations between entry NRTI and MACEs were estimated using a marginal Cox proportional hazards model. Change of NRTI, or "switching," was common during follow-up. Additional associations were estimated by further censoring at first switch and applying time-updated inverse probability of censoring weighting (IPCW). Results: Baseline-adjusted associations suggest clinically relevant increases in hazard of first MACE for ABC versus TAF (hazard ratio [HR], 1.5 [95% confidence interval {CI}, .9-2.3]) and ABC versus TDF (HR, 1.4 [95% CI, .9-2.1]), but not TAF versus TDF (HR, 0.9 [95% CI, .6-1.5]). With censoring at switch, HRs increased to 1.6 (95% CI, .9-2.7) for ABC versus TAF, 2.0 (95% CI, 1.2-3.4) for ABC versus TDF, and 1.2 (95% CI, .7-2.2) for TAF versus TDF. The largest HR observed was for ABC versus TDF and myocardial infarction (IPCW HR, 3.5 [95% CI, 1.3-9.4]). Conclusions: Antiretroviral therapies with ABC backbones are associated with an increase in MACE compared to TFV backbones among people living with HIV at low-to-moderate cardiovascular risk. Clinical Trials Registration: NCT02344290.